Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-18
2003-08-19
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06608207
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing a substituted alkylamine derivative useful as an intermediate for medicine or agricultural chemical. More particularly, the present invention relates to a process for producing a substituted alkylamine derivative or an acid addition salt thereof from a 2-aminothiophenol derivative at a satisfactory yield industrially.
BACKGROUND ART
1-(2-benzothiazolyl)alkylamine derivatives have been known as substituted alkylamine derivatives each having a condensed heterocyclic ring. As a method for synthesis thereof, there is known a condensation reaction between a 2-aminothiophenol derivative and an amino acid-N-carboxyanhydride (see JP-A-8-325235). This method, however, has had a problem in that particular compounds such as (RS)-1-(6-fluoro-2-benzothiazolyl)ethylamine and the like are impossible to produce at a satisfactory yield. The method has further had problems in that the 2-aminothiophenol derivative used as a raw material has a strong odor of hydrogen sulfide and is unstable in the air; in particular, a fluorine-substituted 2-aminothiophenol derivative has a very strong odor, is unstable in such an extent that the derivative forms a disulfide easily even when the air is cut off, and is difficult to handle industrially; and yet use of such a compound is inevitable.
The 2-aminothiophenol derivative used as a raw material in the above reaction can ordinarily be produced easily at a high yield by hydrolyzing a substituted benzothiazole derivative with an alkali metal hydroxide such as potassium hydroxide or the like; in this case, however, the product is obtained as an alkali metal salt and shows alkaline. Meanwhile, the amino acid-N-carboxyanhydride also used as a raw material in the above reaction decomposes easily in the presence of an alkali to become an oligomer. Therefore, the 2-aminothiophenol derivative alkali metal salt synthesized in the above method need be made neutral or acidic. However, when hydrochloric acid or the like is added to the 2-aminothiophenol derivative alkali metal salt to convert the salt into a free 2-aminothiophenol derivative, a disulfide is formed, making very low the yield of the intended product.
For betterment scheme of the above problem, it was found out that a 1-(2-benzothiazolyl)alkylamine derivative can be obtained at a high yield by converting a 2-aminothiophenol derivative into its metal salt (e.g. a zinc salt) stable in the air and of no odor, reacting the metal salt with an amino acid-N-carboxyanhydride and conducting cyclization (see Published International Application WO 99/16759). In this method, however, there is a problem that the metal salt (e.g. a zinc salt) generated as a by-product is mixed into a waste water and the disposal of the waste water bears a larger burden; filtration and drying are necessary in taking-out of 2-aminothiophenol derivative metal salt; and so on, thus, the method is complicated and is difficult to employ industrially.
The present invention aims at providing a process for producing a 1-(2-benzothiazolyl)alkylamine derivative, i.e. a substituted alkylamine derivative from a 2-aminothiophenol derivative easily at a satisfactory yield industrially without giving rise to environmental pollution and the like.
DISCLOSURE OF THE INVENTION
The present inventors made a study in order to solve the problems of the prior art. As a result, the present inventors paid attention to making a 2-aminothiophenol derivative acidic and successfully found out that a 2-aminothiophenol derivative can unexpectedly be made acidic with no substantial formation of a disulfide by adding an alkali salt of a 2-aminothiophenol derivative into an acid. The present inventors further found out that while a reaction between a 2-aminothiophenol derivative formed and an amino acid-N-carboxyanhydride requires the presence of an acid, this reaction proceeds with no need of adding an acid newly if the reaction system is maintained acidic when the salt of a 2-aminothiophenol derivative is added into an acid beforehand, and an intended product can be obtained at a high yield; that the reaction is very friendly to the environment because it generates no metal (e.g. zinc)-containing waste water as a by-product and, in the reaction with an amino acid-N-carboxyanhydride, requires no organic solvent; and that the reaction can be conducted in one pot (in one reactor) from the operation of adding a salt of a 2-aminothiophenol derivative into an acid to the completion of a reaction between a 2-aminothiophenol derivative and an amino acid-N-carboxyanhydride and is very easy to carry out, etc. The above findings led to the completion of the present invention.
The above aim has been achieved by the following inventions [1] to [8].
[1] A process for producing a substituted alkylamine derivative represented by the following general formula (3):
(wherein X is a halogen atom, an alkyl group, an alkoxy group, a cyano group or a nitro group; n is an integer of 1 to 4; and R
1
and R
2
are each independently a hydrogen atom or a phenyl group-substituted or unsubstituted alkyl group and may together form a 5- or 6-membered ring), which process comprises adding a salt of a 2-aminothiophenol derivative represented by the following general formula (1):
(wherein X and n have the same definitions as given above) into an acid to allow the system to have a pH of 6 or less and convert the salt into a free 2-aminothiophenol derivative of the general formula (1) and then reacting the 2-aminothiophenol derivative with an amino acid-N-carboxyanhydride represented by the following general formula (2):
(wherein R
1
and R
2
each have the same definitions as given above).
[2] A process for producing a substituted alkylamine derivative represented by the following general formula (3):
(wherein X is a halogen atom, an alkyl group, an alkoxy group, a cyano group or a nitro group; n is an integer of 1 to 4; and R
1
and R
2
are each independently a hydrogen atom or a phenyl-substituted or unsubstituted alkyl group and may together form a 5- or 6-membered ring), which process comprises adding a salt of a 2-aminothiophenol derivative represented by the following general formula (1):
(wherein X and n have the same definitions as given above) into an acid to allow the system to have a pH of 6 or leas and convert the salt into a free 2-aminothiophenol derivative of the general formula (1) and then reacting, in water or a water-organic solvent mixed solvent, the 2-aminothiophenol derivative with an amino acid-N-carboxyanhydride represented by the following general formula (2):
(wherein R
1
and R
2
each have the same definitions as given above).
[3] A process for producing a substituted alkylamine derivative according to [2], wherein the reaction between the 2-aminothiophenol derivative and the amino acid-N-carboxyanhydride is conducted under an acidic condition.
[4] A process for producing a substituted alkylamine derivative according to [3], wherein the reaction between the 2-aminothiophenol derivative and the amino acid-N-carboxyanhydride is conducted at a pH of 6 or less.
[5] A process for producing a substituted alkylamine derivative according to [1] or [2], wherein the X is a halogen atom.
[6] A process for producing a substituted alkylamine derivative according to [1] or [2], wherein the X is a fluorine atom.
[7] A process for producing a substituted alkylamine derivative according to [1] or [2], wherein the salt of a 2-aminothiophenol derivative is an alkali metal salt of thiophenol.
[8] A process for producing a substituted alkylamine derivative according to [1] or [2], wherein the salt of a 2-aminothiophenol derivative is produced by hydrolyzing a benzothiazole derivative represented by the following general formula (4):
(wherein X and n have the same definitions as given above) with an alkali metal hydroxid
Ihara Chemical Industry Co. Ltd.
Kubovcik & Kubovcik
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